Open Journal of Pathology, 2013, 3, 113-116
Published Online July 2013 (http://www.scirp.org/journal/ojpathology)
http://dx.doi.org/10.4236/ojpathology.2013.33020
113
Pleomorphic Adenoma with Exuberant Squamous
Metaplasia and Keratin Cysts Mimicking Squamous Cell
Carcinoma in Minor Salivary Gland
Sharon Lim1, Inju Cho1, Jun-Hee Park2, Sung-Chul Lim1
1
Department of Pathology, Chosun University College of Medicine, Gwangju, South Korea; 2Department of Otorhinolaryngology,
Chosun University College of Medicine, Gwangju, South Korea.
Email: [email protected]
Received April 4th, 2013; revised May 24th, 2013; accepted June 25th, 2013
Copyright © 2013 Sharon Lim et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Salivary gland tumors, the second most common neoplasm of the mouth after squamous cell carcinoma, account for a
significant proportion of tumors of the oral and perioral regions. An unusual case of adenoma presented as a solitary
intraoral palatine mass in a 32-year-old woman is reported here. The tumor was interpreted as an unusual pleomorphic
adenoma because of the presence of exuberant squamous metaplasia, clinically mimicking squamous cell carcinoma.
Moreover, the presence of cystic structures filled with keratinized material was also salient feature. Pleomorphic adenomas may occasionally display focal squamous metaplastic changes; when extensive, it presents the potential for misinterpretation of the histology as indicative of well-differentiated squamous cell carcinoma.
Keywords: Pleomorphic Adenoma; Squamous Metaplasia; Keratin Cyst; Squamous Cell Carcinoma; Salivary Gland
1. Introduction
Histological diversity is the hallmark of pleomorphic
adenoma (PA). Its histological patterns may vary considerably among different parts of the same tumor [1]. Not
only does the proportion between epithelial and chondromyxoid stroma vary, but some metaplastic variations
also occur in the epithelial and stromal components. Thus,
morphological diversity may often cause a diagnostic problem in surgical pathology due to the limited or selective sampling [2,3].
Squamous metaplasia can be experimentally induced
in the salivary gland following arterial ligation [4,5],
radiation [6], and carcinogen exposure [5,7]. Focal squamous metaplasia may be found in about 25% of the PA
[8], while florid squamous metaplasia is known to occur
rarely [9]. Adnexal differentiation in the form of keratin-filled cysts is also evident in salivary gland [9,10].
Exuberant squamous metaplastic changes in PA present the potential for its misinterpretation as a squamous
cell carcinoma. Squamous cell carcinoma as a collision
tumor or carcinoma ex PA must be considered in the
differential diagnosis. Our study emphasizes the need for
a cautious and systematic approach in the histopathologic
Copyright © 2013 SciRes.
interpretation of the squamous component to avoid misdiagnosis and subsequent overtreatment of PA.
PA with exuberant squamous metaplasia and keratinfilled cysts may cause diagnostic confusion that stresses
the need for a guarded approach while interpreting such
lesions. In this study, we present an unusual case of PA
with exuberant squamous metaplasia and keratin cysts
formations in a minor salivary gland, and discuss its pathogenesis, potential diagnostic pitfalls, proliferative activity, and cytokeratin expression.
2. Case Report
A 32-year-old woman presented to the hospital under the
impression of palatine tumor for further evaluation and
treatment. She had a three-month history of painless
mass on the right side of the soft palate. No history of
surgery, trauma, or infection was evidenced. On physical
examination, a soft tissue mass in the soft palate was
palpated (Figure 1). Radiographic examination showed a
relatively well-defined high signal intensity mass with
internal cystic component in the right side of the soft
palate (Figure 2). Bony erosion in the adjacent region of
right maxilla was identified. There was no visible cerviOJPathology
114
Pleomorphic Adenoma with Exuberant Squamous Metaplasia and Keratin Cysts Mimicking Squamous
Cell Carcinoma in Minor Salivary Gland
Figure 1. Gross finding. Intraoral palatine mass was identified in the right side of the soft palate.
Figure 3. Histopathologic findings. (a) Typical findings of
benign mixed tumor composed of both epithelial and
myoepithelial cells in a myxoid mesenchymal background;
(b) Cords or trabecular arrangement of pseudoinfiltrative
squamous cells around the keratin cyst (KC) mimick welldifferentiated squamous cell carcinoma; (c) Squamoid area
consists of vague lumens, keratin lamellae and peripheral
myoepithelial cells; (d) Remote area from the keratin cyst
showing squamous cell differentiation. Scale bars measure
100 μm (a) and (c) and 200 μm (b) and (d). Hematoxylin &
Eosin staining.
Figure 2. CT scan showed a relatively well-defined high signal intensity mass with internal cystic component.
cal lymphadenopathy. Histopathologic diagnosis on a
punch biopsy was done as PA arising in the minor salivary gland. Complete mass excision was undertaken 16
days after biopsy. The mass was whitish yellow and measured 3.5 × 3.0 × 2.0 cm. Histopathologic findings
showed a relatively well-circumscribed typical benign
mixed tumor composed of both epithelial and myoepithelial cells in a myxoid mesenchymal background. More
than 45% of the epithelial element in the tumor was
composed of sheets of squamous cells with superficial
and deep-seated keratin cysts. The epithelial component
of the tumor formed solid sheets, nests, finger-like projections or cords, and ductal structures (Figure 3).
A double layer of cells lined the ductal component.
Outer cells showed positive immunoreactivity for p63,
S-100 protein, and high-molecular weight (Hmw) cytokeratin (CK), but negative for CK7 and CK19. Inner
cells showed positive immunoreactivity for CK7 and
CK19, but negative for p63, S-100 protein, and Hmw
CK.
Epithelial component not having lumen composed of
squamous cells with distinct intercellular junctions or
Copyright © 2013 SciRes.
keratin pearls, squamoid cells, and keratin cyst containing keratotic lamellae. These cells showed focal immunoreactivity for CK7, CK19, Hmw CK, or S-100 protein.
Cells in the basal layer exhibited positive p63 immunoreactivity (Figure 4).
Cellular proliferation indices, calculated as the percentage of Ki-67 positive tumor cells, were low either in
the typical PA area (1.6%) or in the squamous area with
keratin cyst (1.8% - 2.6%) (Figure 5).
According to the morphological findings and clinical
history, in addition to PA with exuberant squamous metaplasia, squamous cell carcinoma and reactive squamous hyperplasia must also be considered in the differential diagnosis. But, immunohistochemical profiles support the diagnosis of PA with exuberant squamous metaplasia. The postoperative course was uneventful, and no
evidence of disease recurrence was seen 10 months after
surgery.
3. Discussion
Presence of squamoid or frankly squamous epithelia is a
common feature of a number of reactive or neoplastic
conditions of the salivary glands. Depending on the reactive conditions, chronic sialadenitis [11], radiation change
of salivary glands [6], and necrotizing sialometaplasia
[12,13] can be associated with the squamous metaplasia,
while neoplastic conditions associate these cells with
OJPathology
Pleomorphic Adenoma with Exuberant Squamous Metaplasia and Keratin Cysts Mimicking Squamous
Cell Carcinoma in Minor Salivary Gland
Figure 4. Immunohistochemical staining for cytokeratin 7.
Focal immunoreactivity was identified in the squamous
area, but diffuse strong immunoreactivity was noted in the
area of ductal differentiation (right). Scale bar measures
200 μm. ABC method counterstained by hematoxylin.
Figure 5. Cellular proliferation index. Immunostaining for
Ki-67 showed low index (<5%). Scale bar measures 200 μm.
ABC method counterstained by hematoxylin.
mucoepidermoid carcinoma, PA, basal cell adenoma, and
Warthin’s tumor [14,15].
PA is characterized by great histologic diversity; however, PA with exuberant squamous metaplasia is uncommon and can be diagnostically challenging [1-3,9].
Focal squamous metaplasia in PA can be related to
ischemia [16], and may be found in about 25% of the PA
[8]. The present case showed exuberant squamous proliferation in the deep as well as in the superficial regions.
Thus, squamous cell carcinoma should always be considered in the differential diagnosis. A collision tumor
consisting of squamous cell carcinoma arising in the
overlying squamous mucosa epithelia of PA and squamous cell carcinoma ex PA are possible. Moreover, the
present case had a history of previous biopsy 16 days ago.
Hence, exuberant reactive squamous hyperplasia should
be ruled out before clinical diagnosis. The previous biopsy showed intact overlying squamous epithelium withCopyright © 2013 SciRes.
115
out atypia. Therefore, it is very important whether the
squamous component of the PA is malignant or not.
Squamous component also contained areas that showed
mild cellular atypia characterized by some prominent
nucleoli and hyperchromasia, but the proliferation indices (Ki-67 labeling indices) were not high (<5%) in all of
the squamous areas. Benign nature of this tumor is identified by the absence of significant cellular atypia, metastasis and tumor necrosis, and low cellular proliferative
index.
The squamous epithelium lining the keratin cyst formations was homogenously positive for Hmw CK. However, some cells expressed low-molecular weight (Lmw)
CK (CK7 and CK19) and p63. The pattern of CK expression suggests that the cells that express Hmw CK
have undergone squamous metaplasia, but those expressing Lmw CK and p63 have not yet undergone
squamous metaplasia. These morphologically similar
squamoid cells are metaplastic squamous cells and ductal
epithelial cells showing squamoid features depending on
the immunohistochemical and morphologic profiles, respectively. If the squamoid areas were squamous cell
carcinoma or reactive squamous hyperplasia, Lmw CK
and p63 were not expressed in the present case. Therefore, squamoid areas forming keratin pearls or distinct
intercellular junctions and keratin cysts containing keratin lamellae are areas of metaplasia of the PA.
Some areas of the squamous component showed squamous epithelium-lined keratin cysts. Previous reports
[8,17] have designated the similar lesion as adnexal differentiation because of the histologic patterns mimicking
skin appendages. The reported adnexal differentiation
was mainly composed of squamous cells, devoid of glandular differentiation including duct-like formations and
myoepithelial cells, which are present in our demonstrated
case by means of morphological and immunohistochemical aspects. The squamous metaplasia exhibited keratinized cysts containing keratin lamellae and squamous cell islands forming keratin pearls or distinct intercellular junctions in some areas.
PAs, particularly of minor glands of palate, may contain large areas of squamous and mucinous metaplasia
suspicious of squamous cell carcinoma or mucoepidermoid carcinoma. To prevent the misdiagnosis of PA with
exuberant squamous metaplasia as squamous cell carcinoma, cautious and systematic approach in the histopathologic interpretation of the squamous component is
needed.
REFERENCES
[1]
C. Margaritescu, M. Raica, M. Florescu, C. Simionescu,
M. Surpateanu, F. Jaubert and F. Bogdan, “The Ultrastructural Aspects of Neoplastic Myoepithelial Cell in
OJPathology
116
Pleomorphic Adenoma with Exuberant Squamous Metaplasia and Keratin Cysts Mimicking Squamous
Cell Carcinoma in Minor Salivary Gland
Pleomorphic Adenomas of Salivary Glands,” Journal of
Cellular and Molecular Medicine, Vol. 8, No. 3, 2004, pp.
369-381. doi:10.1111/j.1582-4934.2004.tb00326.x
[2]
[3]
[4]
M. Batrani, M. Kaushal, A. K. Sen, R. Yadav and N. K.
Chaturvedi, “Pleomorphic Adenoma with Squamous and
Appendageal Metaplasia Mimicking Mucoepidermoid
Carcinoma on Cytology,” CytoJournal, Vol. 6, 2008, p. 5.
doi:10.4103/1742-6413.45496
V. C. Araujo, S. O. M. Souza, Y. R. Carvalho and N. S.
Araujo, “Application of Immunohistochemistry to the Diagnosis of Salivary Gland Tumors,” Applied Immunohistochemistry and Molecular Morphology, Vol. 8, No. 3,
2000, pp. 195-202.
doi:10.1097/00022744-200009000-00005
S. M. Standish and W. G. Shafer, “Serial Histologic Effects of Rat Submaxillary and Sublingual Salivary Gland
Duct and Blood Vessel Ligation,” Journal of Dental Research, Vol. 36, No. 6, 1957, pp. 866-879.
doi:10.1177/00220345570360060801
[5]
A. Englander and E. Cataldo, “Experimental Carcinogenesis in Duct-Artery Ligated Rat Submandibular Gland,”
Journal of Dental Research, Vol. 55, No. 2, 1976, pp.
229-234. doi:10.1177/00220345760550021101
[6]
M. Friedman and J. W. Hall, “Radiation-Induced Squamous-Cell Metaplasia and Hyperplasia of the Normal
Mucous Glands of the Oral Cavity,” Radiology, Vol. 55,
No. 6, 1950, pp. 848-851.
[7]
S. M. Standish, “Early Histologic Changes in Induced Tumors of the Submaxillary Salivary Glands of the Rat,”
American Journal of Pathology, Vol. 33, No. 4, 1957, pp.
671-689.
[8]
G. Seifert, K. Donath and G. Jautzke, “Unusual Choristoma of the Parotid Gland in a Girl. A Possible Trichoadenoma,” Virchows Archives, Vol. 434, No. 4, 1999, pp.
355-359. doi:10.1007/s004280050352
[9]
E. F. Brachtel, B. Z. Pilch, U. Khettry, A. Zembowicz and
W. C. Faquin, “Fine-Needle Aspiration Biopsy of a Cystic Pleomorphic Adenoma with Extensive Adnexa-Like
Differentiation: Differential Diagnostic Pitfall with Mucoepidermoid Carcinoma,” Diagnostic Cytopathology, Vol.
28, No. 2, 2003, pp. 100-103.
doi:10.1002/dc.10240
Copyright © 2013 SciRes.
[10] N. Siddaraju, P. Murugan, D. Basu and S. K. Verma, “Preoperative Cytodiagnosis of Cystic Pleomorphic Adenoma
with Squamous Metaplasia and Cholesterol Crystals: A
Case Report,” Acta Cytologica, Vol. 53, No. 1, 2009, pp.
101-104. doi:10.1159/000325093
[11] J. L. Jensen, F. V. Howell, G. M. Rick and R. W. Correll,
“Minor Salivary Gland Calculi. A Clinicopathologic Study of Forty-Seven New Cases,” Oral Surgery, Oral Medicine, and Oral Pathology, Vol. 47, No. 1, 1979, pp. 44-50.
doi:10.1016/0030-4220(79)90100-2
[12] A. M. Abrams, R. J. Melrose and F. V. Howell, “Necrotizing Sialometaplasia: A Disease Simulating Malignancy,” Cancer, Vol. 32, No. 1, 1973, pp. 130-135.
doi:10.1002/1097-0142(197307)32:1<130::AID-CNCR28
20320118>3.0.CO;2-8
[13] R. Kruger and H. G. Dietrich, “Salivary Gland Infarction
(Necrotizing Sialometaplasia)-Differential Diagnosis and
Pathogenesis,” Pathologe, Vol. 3, No. 6, 1982, pp. 342347.
[14] E. F. Brachtel, B. Z. Pilch, U. Khettry, A. Zembowicz and
W. C. Faquin, “Fine-Needle Aspiration Biopsy of a Cystic Pleomorphic Adenoma with Extensive Adnexa-Like
Differentiation: Differential Diagnostic Pitfall with Mucoepidermoid Carcinoma,” Diagnostic Cytopathology, Vol.
28, No. 2, 2003, pp. 100-103. doi:10.1002/dc.10240
[15] I. Paker, D. Yilmazer, A. T. Arikok, G. Saylam and S.
Hucumenoglu, “Basal Cell Adenoma with Extensive
Squamous Metaplasia and Cellular Atypia: A Case Report with Cytohistopathological Correlation and Review
of the Literature,” Diagnostic Cytopathology, Vol. 40, No.
1, 2012, pp. 48-55. doi:10.1002/dc.21584
[16] I. Dardick, M. T. Jeans, N. M. Sinnott, J. F. Wittkuhn, H.
J. Kahn and R. Baumal, “Salivary Gland Components
Involved in the Formation of Squamous Metaplasia,”
American Journal of Pathology, Vol. 119, No. 1, 1985,
pp. 33-43.
[17] N. Siddaraju, P. Murugan, D. Basu and S. K. Verma,
“Preoperative Cytodiagnosis of Cystic Pleomorphic Adenoma with Squamous Metaplasia and Cholesterol Crystals: A Case Report,” Acta Cytologica, Vol. 53, No. 1,
2009, pp. 101-104. doi:10.1159/000325093
OJPathology